Fat-specific insulin receptor deletion confers obesity resistance, increased insulin sensitivity, and prolonged lifespan in mice. The Cre-lox system used previously is limited by inconsistent gene deletion, potential ectopic Cre expression in macrophages driven by the Ap2 promoter used, and constitutive deletion starting in embyronic life. We are developing transgenic models using alternate fat specific promoters (adiponectin, perilipin) to drive expression of constitutive and inducible Cre recombinases to achieve more tissue specificity and temporal control over recombination. We will characterize these models and use them to: Confirm the metabolic phenotype without confounding by possible macrophage effects. Investigate the role of adipocyte insulin signaling in maintenance of established fat depots. Determine whether disruption of insulin signaling in adipocytes of adult animals can reproduce the metabolic phenotype of the constitutive knockout. Dissect the role of adipocyte insulin signaling versus adiposity in the metabolic phenotype of FIRKO mice. Compare gene expression changes after interruption of adipocyte insulin signaling in adult mice with our gene array data from constitutive fat-specific insulin receptor knockout mice at various ages. [unreadable] [unreadable] [unreadable]